Complement component c3 irna compositions and methods of use thereof

Abstract

The present invention relates to RNAi agents, e.g., double stranded RNA (dsRNA) agents, targeting the complement component C3 gene (C3). The invention also relates to methods of using such RNAi agents to inhibit expression of a C3 gene and to methods of preventing and treating a C3-associated disorder, e.g., cold agglutinin disease (CAD), warm autoimmune hemolytic anemia, and paroxysmal nocturnal hemoglobinuria (PNH), lupis nephritis (LN), bullous pemphigoid, pemphigus, e.g., pemphigus vulgaris (PV) and pemphigus foliaceus (PF), and C3 glomerulopathy.

1 . A double stranded ribonucleic acid (dsRNA) agent, or a salt thereof, for inhibiting expression of complement component C3 in a cell, wherein;
 (a) the dsRNA agent, or a salt thereof, comprises a sense strand and an antisense strand forming a double stranded region, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO: 1 and the antisense strand comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from the nucleotide sequence of SEQ ID NO:5;   (b) the dsRNA agent, or a salt thereof, comprises a sense strand and an antisense strand forming a double stranded region, wherein the antisense strand comprises a region of complementarity to an mRNA encoding complement component C3, and wherein the region of complementarity comprises at least 15 contiguous nucleotides differing by no more than 3 nucleotides from any one of the antisense nucleotide sequences in any one of Tables 2-7, 15, 18, 20-23, 30, and 31: or   (c) wherein the dsRNA agent, or a salt thereof, comprises a sense strand and an antisense strand forming a double stranded region, wherein the sense strand comprises at least 15 contiguous nucleotides differing by no more than three nucleotides from any one of the nucleotide sequence of nucleotides 475-497, 487-509, 490-512, 491-513, 705-727, 809-831, 813-835, 1147-1169, 1437-1459, 1439-1461, 1447-1469, 2596-2618, 2634-2656, 3012-3034, 3334-3356, 3611-3633, 3614-3636, 3622-3655, 3809-3831, 3846-3868, 3847-3869, 3920-3942, 4047-4069, 4061-4083, 4156-4178, 4157-4177, 4162-4184, 4178-4200, 4226-4248, 4369-4391, 4392-4414, 4521-4543, 4522-4544, 4523-4545, 5012-5034 of the nucleotide sequence of SEQ ID NO:1, and the antisense strand comprises at least 19 contiguous nucleotides from the corresponding nucleotide sequence of SEQ ID NO:5.   
     
     
         2 - 8 . (canceled) 
     
     
         9 . The dsRNA agent, or a salt thereof, of  claim 1 , wherein the dsRNA agent, or a salt thereof, comprises at least one modified nucleotide modification. 
     
     
         10 . (canceled) 
     
     
         11 . The dsRNA agent, or a salt thereof, of  claim 1 , wherein all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand comprise a nucleotide modification. 
     
     
         12 . The dsRNA agent, or a salt thereof, of  claim 1 , wherein at least one of the nucleotide modifications is selected from the group consisting of a deoxy-nucleotide modification, a 3′-terminal deoxy-thymine (dT) nucleotide modification, a 2′-O-methyl nucleotide modification, a 2′-fluoro nucleotide modification, a 2′-deoxy nucleotide modification, a locked nucleotide modification, an unlocked nucleotide modification, a conformationally restricted nucleotide modification, a constrained ethyl nucleotide modification, an abasic nucleotide modification, a 2′-amino nucleotide modification, a 2′-O-allyl nucleotide modification, 2′-C-alkyl nucleotide modification, 2′-hydroxyl nucleotide modification, a 2′-methoxyethyl nucleotide modification, a 2′-O-alkyl-modified nucleotide modification, a morpholino nucleotide modification, a phosphoramidate modification, a non-natural base comprising nucleotide modification, a tetrahydropyran nucleotide modification, a 1,5-anhydrohexitol nucleotide modification, a cyclohexenyl nucleotide modification, a nucleotide comprising a phosphorothioate group modification, a nucleotide comprising a methylphosphonate group modification, a nucleotide comprising a 5′-phosphate modification, a nucleotide comprising a 5′-phosphate mimic modification, a thermally destabilizing nucleotide modification, a glycol nucleotide (GNA) modification, and a 2-O-(N-methylacetamide) nucleotide modification; and combinations thereof. 
     
     
         13 - 16 . (canceled) 
     
     
         17 . The dsRNA agent, or a salt thereof, of  claim 1 , wherein the double stranded region is 19-30 nucleotide pairs in length. 
     
     
         18 - 21 . (canceled) 
     
     
         22 . The dsRNA agent, or a salt thereof, of  claim 1 , wherein each strand is independently no more than 30 nucleotides in length. 
     
     
         23 - 26 . (canceled) 
     
     
         27 . The dsRNA agent, or a salt thereof, of  claim 1 , wherein at least one strand comprises a 3′ overhang of at least 1 nucleotide, or at least one strand comprises a 3′ overhang of at least 2 nucleotides. 
     
     
         28 . (canceled) 
     
     
         29 . The dsRNA agent, or a salt thereof, of  claim 1 , further comprising a ligand. 
     
     
         30 . The dsRNA agent, or a salt thereof, of  claim 29 , wherein the ligand is conjugated to the 3′ end of the sense strand of the dsRNA agent, or a salt thereof. 
     
     
         31 . The dsRNA agent, or a salt thereof, of  claim 29 , wherein the ligand is an N-acetylgalactosamine (GalNAc) derivative. 
     
     
         32 . The dsRNA agent, or a salt thereof, of  claim 29 , wherein the ligand is one or more GalNAc derivatives attached through a monovalent, bivalent, or trivalent branched linker. 
     
     
         33 . The dsRNA agent, or a salt thereof, of  claim 31 , wherein the ligand is 
       
         
           
           
               
               
           
         
       
     
     
         34 . The dsRNA agent, or a salt thereof, of  claim 33 , wherein the dsRNA agent, or a salt thereof, is conjugated to the ligand as shown in the following schematic 
       
         
           
           
               
               
           
         
       
       and, wherein X is O or S. 
     
     
         35 . The dsRNA agent, or a salt thereof, of  claim 34 , wherein the X is O. 
     
     
         36 - 45 . (canceled) 
     
     
         46 . A cell containing the dsRNA agent, or a salt thereof, of  claim 1 . 
     
     
         47 . A pharmaceutical composition for inhibiting expression of a gene encoding complement component C3 comprising the dsRNA agent, or a salt thereof, of  claim 1 . 
     
     
         48 - 52 . (canceled) 
     
     
         53 . An in vitro method of inhibiting expression of a complement component C3 gene in a cell, the method comprising contacting the cell with the dsRNA agent, or a salt thereof, of  claim 1 , thereby inhibiting expression of the complement component C3 gene in the cell. 
     
     
         54 - 59 . (canceled) 
     
     
         60 . A method of treating a subject having a disorder that would benefit from reduction in complement component C3 expression, comprising administering to the subject a therapeutically effective amount of the dsRNA agent, or a salt thereof, of  claim 1 , thereby treating the subject having the disorder that would benefit from reduction in complement component C3 expression. 
     
     
         61 . A method of preventing at least one symptom in a subject having a disorder that would benefit from reduction in complement component C3 expression, comprising administering to the subject a prophylactically effective amount of the dsRNA agent, or a salt thereof, of  claim 1 , thereby preventing at least one symptom in the subject having the disorder that would benefit from reduction in complement component C3 expression. 
     
     
         62 . The method of  claim 60 , wherein the disorder is a complement component C3-associated disorder. 
     
     
         63 . The method of  claim 62 , wherein the complement component C3-associated disorder is selected from the group consisting of cold agglutinin disease (CAD), warm autoimmune hemolytic anemia, paroxysmal nocturnal hemoglobinuria (PNH), lupis nephritis (LN), bullous pemphigoid, pemphigus, pemphigus vulgaris (PV), pemphigus foliaceus (PF), and C3 glomerulopathy. 
     
     
         64 . (canceled) 
     
     
         65 . The method of  claim 62 , wherein the subject is human. 
     
     
         66 - 67 . (canceled) 
     
     
         68 . The method of  claim 60 , wherein the dsRNA agent, or a salt thereof, is administered to the subject subcutaneously. 
     
     
         69 - 70 . (canceled) 
     
     
         71 . The method of  claim 60 , further comprising administering to the subject an additional therapeutic agent for treatment of hemolysis. 
     
     
         72 . A kit, vial, or syringe comprising the dsRNA agent, or a salt thereof, of  claim 1 . 
     
     
         73 - 74 . (canceled)